The Current issue of “The view from here” discusses medicinal chemistry.

The topic of this month’s newsletter from Drug Discovery Today is medicinal chemistry.

Although biotherapeutics have gained significant market penetration in the last 20 years and their value cannot be understated, medicinal chemistry (and medicinal chemists) has not just faded away. In some respect, advances in medicinal chemistry have been some of the most revolutionary aspects of Pharmaceutical science in this period. The contribution of the medicinal chemist has continued to be of paramount importance to the development of new and innovative medicines in this period. Although the discipline of Medicinal Chemistry has significantly changed over this period, fundamentally good science and a background of strong organic chemistry continues to underpin the role.

The free downloads available in this newsletter highlight some of the most recent developments in translational research in drug discovery. I will elaborate on them below.

The first article, by Haijun Chen*, Xiaobin Zhou,  Ailan Wang, Yunquan Zheng, Yu Gao and Jia Zhou* of the College of Chemistry, Fuzhou University, Fuzhou, Fujian 350108, PR China  and  the  Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA* , entitled “Evolutions in fragment-based drug design: the deconstruction– reconstruction approach”  describes  recent advances in the understanding of molecular recognition and protein–ligand interactions and how they have facilitated the rapid development of potent and selective ligands for therapeutically relevant targets. In particular, they outline how a fragment-based drug design (FBDD) approach has enabled rapid and efficient progress in drug discovery. They focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening (FBS) for constructing such libraries while highlighting  the deconstruction–reconstruction strategy by utilizing privileged fragments of reported ligands.

The second article, from Maykel Cruz-Monteagudo, Jose L. Medina-Franco, Yunierkis Perez-Castillo, Orazio Nicolotti, M. Natalia D.S. Cordeiro and Fernanda Borges,  entitled: “Activity cliffs in drug discovery: Dr Jekyll or Mr Hyde?”, discusses the impact  that activity cliffs have on drug discovery and their double-edged nature. For instance, whereas medicinal chemists can take advantage of regions in chemical space rich in activity cliffs, QSAR practitioners need to escape from such regions. The influence of activity cliffs in medicinal chemistry applications is extensively documented. However, the ‘dark side’ of activity cliffs (i.e. their detrimental effect on the development of predictive machine learning algorithms) has been understudied. Similarly, limited amounts of work have been devoted to propose potential solutions to the drawbacks of activity cliffs in similarity-based approaches. In this review, the duality of activity cliffs in medicinal chemistry and computational approaches is addressed, with emphasis on the rationale and potential solutions for handling the ‘ugly face’ of activity cliffs.

Finally, is the review from Frederick W. Goldberg, Jason G. Kettle, Thierry Kogej, Matthew W.D. Perry and Nick P. Tomkinson of AstraZeneca, entitled, “Designing novel building blocks is an overlooked strategy to improve compound quality”.  The authors discuss a pragmatic approach to improve compound quality, while enhancing and accelerating drug discovery projects, through access to high quality, novel, diverse building block collections. They outline those general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects. They highlight an example of a program initiated in 2009 to address this, which has already delivered three candidate drugs, and the success of that program provides evidence that focusing on building block design is a useful strategy for drug discovery.

Steve Carney was born in Liverpool, England and studied Biochemistry at Liverpool University, obtaining a BSc.(Hons) and then read for a PhD on the Biochemistry and Pathology of Connective Tissue Diseases in Manchester University, in the Departments of Medical Biochemistry and Histopathology. On completion of his PhD he moved to the Kennedy Institute of Rheumatology, London, where he worked with Professor Helen Muir FRS and Professor Tim Hardingham, on the biochemistry of experimental Osteoarthritis. He joined Eli Lilly and Co. and held a number of positions in Biology R&D, initially in the Connective Tissue Department, but latterly in the Neuroscience Department. He left Lilly to take up his present position as Managing Editor, Drug Discovery Today, at Elsevier. Currently, he also holds an honorary lectureship in Drug Discovery at the University of Surrey, UK. He has authored over 40 peer-reviewed articles, written several book chapters and has held a number of patents.

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